Pharmacological treatments that facilitate extinction of fear: Relevance to psychotherapy

A great deal is now known about the mechanisms of conditioned fear acquisition and expression. More recently, the mechanisms of inhibition of conditioned fear have become the subject of intensive study. The major model system for the study of fear inhibition in the laboratory is extinction, in which a previously fear conditioned organism is exposed repeatedly to the fear-eliciting cue in the absence of any aversive event and the fear conditioned response declines. It is well established that extinction is a form of new learning as opposed to forgetting or “unlearning” of conditioned fear, and it is hypothesized that extinction develops when sensory pathways conveying sensory information to the amygdala come to engage GABAergic interneurons through forms of experience-dependent plasticity such as long-term potentiation. Several laboratories currently are investigating methods of facilitating fear extinction in animals with the hope that such treatments might ultimately prove to be useful in facilitating exposure-based therapy for anxiety disorders in clinical populations. This review discusses the advances that have been made in this field and presents the findings of the first major clinical study to examine the therapeutic utility of a drug that facilitates extinction in animals. It is concluded that extinction is an excellent model system for the study of fear inhibition and an indispensable tool for the screening of putative pharmacotherapies for clinical use.     

Pericardium as a thoracic aortic patch: glutaraldehyde-fixed and fresh autologous pericardium

The repair of complex coarctation of the aorta often requires an aortic patch. Prosthetic patches lack growth potential and are associated with an increased incidence of aneurysm formation opposite the patch. We compared buffered glutaraldehyde-fixed patches, used in six animals (group 1), and untreated autologous pericardial aortic patches, used in five animals (group 2). Weanling pigs underwent pericardial patch replacement of a 1 X 2-cm diamond-shaped segment of the lateral wall of the descending thoracic aorta at the level of the aortic isthmus. Six months following patch aortoplasty, the animals were killed and the in situ patch dimensions were measured and compared to the measurements obtained at implantation. The increases in length, recorded as mean percentage change +/- SEM, were 34.7 +/- 3.7% for group 1 and 102.8 +/- 20.3% for group 2 animals; the increases in width were 91.4 +/- 31.7% for group 1 and 192.4 +/- 31.4% for group 2. The percentage changes for both length and width were significantly different between groups (P less than 0.05). Pull strength testing of standard-size patch samples demonstrated no significant difference in tensile breaking load between groups: group 1 = 959 +/- 277 g, group 2 = 795 +/- 86 g. Thoracic aortography revealed no evidence of stenosis or aneurysmal dilation in either group. Autologous pericardium is resilient, strong, and readily available and has expansile potential that makes it an ideal aortic patch material. We conclude that glutaraldehyde fixation does not provide additional strength and limits graft expansile potential when compared to untreated pericardium.     

Fever and feeding in the rat: Actions of intrahypothalamic interleukin-6 compared to macrophage inflammatory protein-1β (MIP-1β)

The chemokines, macrophage inflammatory protein-1 (MIP-1) and its subunit MIP-1β, induce an intense fever in the rat when they are injected directly into the anterior hypothalamic, pre-optic area (AH/POA), a region containing thermosensitive neurons. The purpose of this study was to compare the central action on body temperature (T_b) of MIP-1β with that of interleukin-6 (IL-6), which also has been implicated in the cerebral mechanism underlying the pathogenesis of fever. Following the stereotaxic implantation in the AH/POA of guide cannulae for repeated micro-injections, radio transmitters which monitor T_b continuously were inserted intraperitoneally in each of 15 male Sprague-Dawley rats. Each micro-injection was made in a site in the AH/POA in a volume of 1.0 μl of pyrogen-free artificial CSF, recombinant murine MIP-1β, or recombinant human IL-6. MIP-1β in a dose of 25 pg evoked an intense fever characterized by a short latency, a mean maximum rise in T_b of 2.4 ± 0.21°C reached by 3.7 ± 0.42 hr, and a duration exceeding 6.5 hr. Injected into homologous sites in the AH/POA, IL-6 induced a dose dependent fever of similar latency and a mean maximal increase in T_b of 1.2 ± 0.25°C, 1.8 ± 0.15°C, and 2.1 ± 0.22°C and duration of 6.2 ± 1.28 hr, 6.7 ± 0.49 hr, and 6.8 ± 0.65 hr when given in doses of 25, 50, and 100 ng, respectively. These results show that MIP-1β and the highest dose of IL-6 induce a fever of comparable intensity, but MIP-1β exerts its action in a much lower concentration. Thus, the de novo synthesis and subsequent action of the MIP-1 family of cytokines on neurons of the AH/POA in response to a pyrogen challenge apparently play a functional role in the pathogenesis of fever. Further, the endogenous activity of IL-6 in the hypothalamus which is enhanced in response to a lipopolysaccharide also may reflect its essential part in the acute phase response to a bacterial challenge. Copyright © 1994 Wiley-Liss, Inc.     

Pharmacological specificity of the increase in neurotensin concentrations after antipsychotic drug treatment.

Neurotensin is an endogenous neuropeptide that produces many CNS effects that are similar to the behavioral and physiological alterations seen after administration of antipsychotic drugs to laboratory animals. As previously reported, sub-chronic (3 week) and acute (single injection) treatment with haloperidol (1 mg/kg), a clinically effective antipsychotic drug increases neurotensin concentrations in the nucleus accumbens and the caudate nucleus. In contrast, a tricyclic antidepressant (desipramine, 10 mg/kg), an anxiolytic (chlordiazepoxide, 25 mg/kg) and a histamine H1 receptor antagonist (diphenhydramine, 20 mg/kg) did not alter neurotensin concentrations in these brain regions after sub-chronic or acute treatment. These data demonstrate pharmacologic specificity to the antipsychotic drug-induced increases in regional brain neurotensin concentrations, and support the hypothesis that these changes may contribute to the clinical efficacy of these drugs.     

Optometry research. Part 2: Grants received.

Part 1 showed that the dominant provider of ophthalmic research funding (85%) was the National Eye Institute (NEI) and that on the average optometry faculty members had received about 3% of that funding over the years. Part 2 shows how this 3% of NEI funding has been distributed among the 16 U.S. schools in existence during the period studied and why 3% is a rational result under current conditions.     

Artifacts due to stimulus correlated motion in functional imaging of the brain

To assess the effect of stimulus correlated motion on the appearance of functional magnetic resonance images, conventional visual and motor protocols were each performed by four normal volunteers and an image co-registration technique was used to retrospectively monitor subject motion. In three studies synthetic data sets were constructed from single baseline images using the positional information obtained from the co-registration procedure. Cumulative difference images were then created from both the synthetic and functional image sets. Stimulus correlated motion was detected in all eight studies and the synthetic cumulative difference images showed striking similarities to the equivalent functional images in each case.     

Molecular cloning and functional expression of two monocyte chemoattractant protein 1 receptors reveals alternative splicing of the carboxyl-terminal tails.

Monocyte chemoattractant protein 1 (MCP-1) is a member of the chemokine family of cytokines that mediate leukocyte chemotaxis. The potent and specific activation of monocytes by MCP-1 may mediate the monocytic infiltration of tissues in atherosclerosis and other inflammatory diseases. We have isolated cDNAs that encode two MCP-1-specific receptors with alternatively spliced carboxyl tails. Expression of the receptors in Xenopus oocytes conferred robust mobilization of intracellular calcium in response to nanomolar concentrations of MCP-1 but not to related chemokines. The MCP-1 receptors are most closely related to the receptor for the chemokines macrophage inflammatory protein 1 alpha and RANTES (regulated on activation, normal T expressed and secreted). The identification of the MCP-1 receptor and cloning of two distinct isoforms provide powerful tools for understanding the specificity and signaling mechanisms of this important chemokine.